Julie Forman-Kay is Program Head and Senior Scientist in the Molecular Medicine Program at the Research Institute of The Hospital for Sick Children and a Professor in the Biochemistry Department at the University of Toronto. The major focus of her work has been to provide biological insights into how dynamic properties of proteins are related to function and methodological tools to enable better understanding of dynamic and disordered states. Her expertise is in using NMR and other biophysical and computational tools to study dynamic and disordered proteins and their interactions, including characterizing their dynamic complexes that are mediated by multivalent interactions. Approaches for calculating computational representations disordered state ensembles have been developed in her group. A related area of interest is the role of post-translational modification, such as phosphorylation and methylation, in regulating structural and binding properties in disordered states and dynamic complexes.

The Forman-Kay lab works on a number of projects of specific relevance to cancer and neurobiology. Most recently her lab has started to probe the role phase separation of disordered proteins in RNA processing bodies, a key regulatory process for neurological function. Her group also has a strong interest in CFTR, the cystic fibrosis transmembrane conductance regulator, particularly its cytoplasmic domains including the disordered regulatory R region. Her work is highly collaborative and has had significant impact, with widely recognized contributions to the fields of intrinsically disordered proteins, protein interaction domains, and CFTR structure, dynamics and interactions. She is co-chair of the CFTR Structure Consortium of the US Cystic Fibrosis Foundation Therapeutics. She is the recipient of the 2012 CSMB Jeanne Manery Fisher Memorial Lectureship and the 2013 Zellers Senior Scientist Award from Cystic Fibrosis Canada.

Major tools

Research Description

Structural Studies of Disordered Proteins

Disordered Proteins

Structural studies of intrinsically disordered proteins and regions, which play critical biological roles, lag far behind studies of folded proteins. A major focus of my work has been to bridge this gap. We developed the ENSEMBLE program to generate ensembles of conformers representing a disordered state [Marsh & Forman-Kay, Ensemble modeling of protein disordered states: Experimental restraint contributions and validation, Proteins (2012); Krzeminski et al, Characterization of disordered proteins with ENSEMBLE. Bioinformatics (2013)]. Our contributions to the field of disordered states are described in a recent review [Forman-Kay & Mittag, From sequence and forces to structure, function and evolution of intrinsically disordered proteins, 20th anniversary issue of Structure (2013)].

Dynamic Complexes

Disordered proteins often bind targets in highly dynamic complexes. We demonstrated that the disordered Sic1 cyclin dependent kinase inhibitor binds to the Cdc4 component of an SCF ubiquitin ligase complex in a dynamic complex with multiple phosphorylation sites of Sic1 exchanging on and off of the Cdc4 binding site [Mittag et al, Dynamic equilibrium engagement of a polyvalent ligand with a single site receptor, PNAS (2008); Tang et al, Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase, PNAS (2012)] and have calculated models of the free Sic1 and its dynamic complex with Cdc4, shedding insight into the ultrasensitive ubiquitination of Sic1 within the SCF ligase [Mittag et al, Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase, Structure (2010)]. We characterized Abp SH3 domain complexes involved in actin organization and correlated the degree of engagement within the dynamic complexes with functional data [Stollar et al. Structural, functional and bioinformatic studies demonstrate the crucial role of an extended peptide binding site for the SH3 domain of yeast Abp1p. J Biol Chem (2009); Stollar et al, Differential dynamic engagement within 24 SH3 domain:peptide complexes revealed by co-linear chemical shift perturbation analysis, PLoS One (2012)]. We demonstrated a dynamic interaction of 4E-BP2 that is key for translational regulation [Lukhele et al, Interaction of the eukaryotic initiation factor 4E with 4E-BP2 at a dynamic bipartite interface, Structure (2103)].

Importantly, we showed that phosphorylation induces folding of 40 residues of 4E-BP2 to a 4E-binding-incompatible state [Bah et al, Phosphorylation-Induced Folding in an Intrinsically Disordered Protein as a Regulatory Switch, Nature (2014)], the first time significant folding of an IDP due to post-translational modification has been reported. We have also characterized the phase separation of the disordered region of Ddx4, helping to develop this new field that links biophysics and cell biology [Nott et al, Phase transition of a disordered Nuage protein generates environmentally responsive membraneless organelles, Mol Cell (2014)].